Antimicrobial Resistance (AMR) PDF

Antimicrobial Resistance (AMR) “The thoughtless person playing with penicillin treatment is morally responsible for the death of the man who succumbs to infection with the penicillin-resistant organism.” - Alexander Fleming (1945) Simple overview of Antibiotics and Resistance Beta-lactams and mechan...

Antimicrobial Resistance (AMR) “The thoughtless person playing with penicillin treatment is morally responsible for the death of the man who succumbs to infection with the penicillin-resistant organism.” - Alexander Fleming (1945) Simple overview of Antibiotics and Resistance Beta-lactams and mechanism of Resistance Beta-lactams and mechanism of Resistance In the absence of a beta-lactam antibiotic, transpeptidases, also known as penicillin binding proteins catalyze the cross links between glycan changes in the peptidoglycan The result is covalent bonds between the peptide and sugar chains that create a rigid cell wall that protects the bacterial cell from osmotic forces that can result in cell rupture Beta-lactam antibiotics, are similar to the natural peptidoglycan subunits (D-Ala-D-ala) that are the substrate for the transpeptidases. These antibiotics bind strongly to the active site in the transpeptidase and stop cell wall synthesis Penicillin and Synthetic beta-lactams Penicillin and Synthetic beta-lactams All beta-lactam antibiotics contain the same core 4-member betalactam ring. This ring is what mimics the shape of the terminal D-Ala-D-Ala peptide sequence that is the substrate for the transpeptidase Chemical modification of the structure of penicillins led to the sevelopment of synthetic beta-lactams – which have greater spectrums of activity, and greater resistance to beta-lactamases, as well as different pharmacokenetic properties. General Resistance to Beta-Lactams 1. Penetration – Intracellular bacteria are resistant to beta-lactams if they are in a mammalian cell 2. Porins – Gram-negative bacteria are resistant to beta-lactams since the outer cell membrane protects the peptidoglycan, but porins can allow beta-lactams inside. However, some Gram-negatives have smaller porins that excludes beta-lactams (general) 3. Pumps – Gram-negative bacteria can express ABC transporters to pump antibiotics out of the cell 4. Peptidoglycan is absent – Some bacteria like mycobacteria lack a cell wall, and are thus not affected by beta-lactam antibiotics Specific Resistance to Beta-Lactams Specific Resistance to Beta-Lactams Specific Resistance to Beta-Lactams 1. Penicillinases – Some bacteria can make beta-lactamases that degrade beta-lactam antibiotics before they reach the cell 2. PBPs – Some bacteria can express mutated transpeptidases that still has the enzymatic activity for cell wall synthesis, but does not bind to beta-lactam antibiotics Antimicrobial Resistance (AMR) https://www.youtube.com/watch?v=yybsSqcB7mE Key Facts Antibiotic resistance is a multi-level threat to humanity, it has effects on Global health Food Security Development / Economics An antibiotic resistant infection can affect anyone, of any age, in any country regardless of immune status Antibiotic resistance occurs naturally, but overuse of antibiotics in humans and animals has accelerated the process A growing number of infections have become harder to, or impossible to, treat as a result The unavailability of antibiotics will change the entire field of medicine, from making childbirth riskier, to post-operative care, to chemotherapy. By 2050, 10million people will die due to AMR Annually https://amr-review.org/sites/default/files/AMR Review Paper - Tackling a crisis for the health and wealth of nations_1.pdf This will have unprecedented financial impacts https://amr-review.org/sites/default/files/AMR Review Paper - Tackling a crisis for the health and wealth of nations_1.pdf The health crisis will be worse than AIDS, Cancer, or COVID-19 https://amr-review.org/sites/default/files/AMR Review Paper - Tackling a crisis for the health and wealth of nations_1.pdf Antibiotic Resistance (ABR) Antibiotics are widely used in human medicine, agricultural production, and food processing Antimicrobials have been essential for ensuring human health and the health of our food supply However, the rise of incidence of AMR is increasing on a global scale Consumers are concerned about the increased difficulty in treating infections caused by AMR bacteria (few understand the true threat of AMR bacteria) There is a renewed interest in decreasing the antibiotics used agriculture Evidence suggests that the development, dissemination, and persistence of ABR bacteria and their resistance genes is complicated A History of Antibiotic Usage in Agriculture In the USA in the 1910’s non-food-producing urbanites outnumbered farmers, and demand for meat routinely outstripped supply. After WWI in 1917 the USDA funded research aimed at increasing meat production Penicillin was discovered in 1928, at the time all S. aureus were susceptible to this antibiotic Sulphonamides were marketed for routine use in agriculture by 1938 In the 1940’s aureomycin was found to increase the rate at which poultry gained weight Park and Ronholm, 2021 A History of Antibiotic Usage in Agriculture In the 1940’s Britain used antibiotics to treat bovine mastitis to increase milk output In 1948 sulfaquinoxaline was used to prevent coccidiosis in broilers. Antibiotic growth promoters (AGPs) were licensed in the USA in 1951, in Britain in 1953, in the Netherlands in 1954, and in France in 1955. In 1928 basically all S. aureus was susceptible to penicillin, in 1998 95% of S. aureus isolates were resistant to penicillin Today, in North America, most chickens are fed bacitracin and ionophores, and most beef cattle are fed ionophores. Most dairy cattle are treated prophylactically with ceftiofur every lactation. Park and Ronholm, 2021 Is it worth it? Some argue that if animal-based protein were removed tomorrow, most of these issues would go away Use of antibiotics in the dairy industry have led to a 95% reduction in mastitis infections, when compared to the pre-antibiotic era Though other interventions also happened during this time Antibiotic growth promoters (AGPs) increase body weight in broilers by 8% and improve feed efficiency by about 5% The mortality rate in no-antibiotics chickens is about 4.2% compared with 2.9% in conventionally raised broilers No-antibiotics birds also show higher levels of eye burns, footpad lesions, and airsacculitis – each of which is an indicator of poor welfare Also, no-antibiotic birds present environmental concerns due to needing extra acres of field and water required for poultry production AGPs improve pig growth rate by 4.2% and feed efficiency by 2.2% Park and Ronholm, 2021 WHO Response The WHO has a five-pronged approach to combatting AMR: To improve awareness and understanding of antimicrobial resistance. To strengthen surveillance and research. To reduce the incidence of infection. To optimize the use of antimicrobial medicines. To ensure sustainable investment in countering antimicrobial resistance. Canada’s Response Canada as a three-pronged approach to combatting AMR: Surveillance: Detecting and monitoring trends and threats in order to inform strategies to reduce the risks and impacts of antimicrobial resistance Stewardship: Conserving the effectiveness of existing treatments through infection prevention and control guidelines, education and awareness, regulations, and oversight Innovation: Creating new solutions to counteract the loss in antimicrobial effectiveness through research and development https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/federal-action-plan-antimicrobial-resistance-canada.html Canada’s Approach to Stewardship Categorizing antibiotics into 4 categories based on their importance in human medicine to help prioritize risk management options AMR specific warnings on Category I, II, and III drugs Supporting the microbiological safety evaluation of veterinary antimicrobial drugs using CIPARS data Encouraging prudent use of antimicrobials Undertaking post-market re-evaluation of medically important antibiotics over time Canada’s Approach to Stewardship Canada categorizes antibiotics based on their importance to human medicine. https://www.canada.ca/en/health-canada/services/drugs-health-products/veterinary-drugs/antimicrobial-resistance/categorization-antimicrobial-drugs-based-importance-human-medicine.html https://www.canada.ca/en/health-canada/services/drugs-health-products/veterinary-drugs/antimicrobial-resistance/categorization-antimicrobial-drugs-based-importance-human-medicine.html https://www.canada.ca/en/health-canada/services/drugs-health-products/veterinary-drugs/antimicrobial-resistance/categorization-antimicrobial-drugs-based-importance-human-medicine.html https://www.canada.ca/en/health-canada/services/drugs-health-products/veterinary-drugs/antimicrobial-resistance/categorization-antimicrobial-drugs-based-importance-human-medicine.html https://www.canada.ca/en/health-canada/services/drugs-health-products/veterinary-drugs/antimicrobial-resistance/categorization-antimicrobial-drugs-based-importance-human-medicine.html Categorization effectiveness? A Category I antibiotic (Ceftiofur) is still used prophylactically in dairy cattle And Category III and IV antibiotics are still used in poultry feed Instances of cross-reaction have been observed Synercid is a semi-synthetic antibiotic that is approved to treat MRSA infections in humans Virginiamycin is approved for feed in broiler chickens and swine Virginiamycin acetyltransferases confer resistance to Synercid MCR-1 confers resistance to colistin and bacitracin Bacitracin is often used in agricultural ecosystems Park and Ronholm, 2021 Canada’s Approach to Surveillance https://www.canada.ca/en/public-health/services/surveillance/canadian-integrated-program-antimicrobial-resistance-surveillance-cipars/cipars-reports/2018-annual-report-integrated-findings.html Canada’s Approach to Surveillance In 2014 the poultry industry was banned from using ceftiofur in hatchlings. The action was taken in response to growing detection of Salmonella and E. coli resistant to 3rd generation cephalosporins. CIPARS Effectiveness https://www.canada.ca/content/dam/phac-aspc/migration/phac-aspc/cipars-picra/heidelberg/gfx/f1b-eng.gif CIPARS Are we missing anything that is important in the non-pathogen data? Where do we go from here? Replacing Antibiotics Improved hygiene Vaccinations (and new vaccinations) Bacteriophages Probiotics And new targeted probiotics Antibiotic derivatives Antagonistic Inter-Bacterial Interactions